In the gastrointestinal tract, ionic balance, fluid absorption, and secretion are vital to maintain homeostasis allowing for the maintenance of a membrane potential, adequate nutrient intake, normal gut motility, protection against microbes, and epithelial cell viability. This homeostatic state relies on the normal physiological function of the small and large intestinal cells and a complex array of hormonal mechanisms that control gut motility as well as entry and exit of fluid into the gastrointestinal lumen. Approximately, 8–10 L of fluid pass through the small intestinal lumen daily. It is remarkable that in health, the small intestine absorbs all but 1.5 L and the colon absorbs the rest leaving approximately 100 mL of fluid to be lost in stool. Intestinal ion transport mechanisms play a significant role in determining overall fluid balance in the gut, namely chloride secretion, electroneutral sodium chloride absorption and electrogenic sodium absorption. Moreover, a variety of hormones and neurotransmitters are synthesized locally in the intestinal mucosa and modify intestinal ion transport either directly by binding to receptors on the basolateral membrane of enterocytes or indirectly via the release of other effectors. In certain pathophysiologic states, the finely tuned ionic-fluid exchange becomes dysfunctional as a result of the failure of compensatory pro-absorptive/antisecretory mechanisms. Different pathophysiological mechanisms causing diarrhea, mainly secretory, osmotic, inflammatory, altered intestinal transit and loss of functional absorptive area, have been elucidated.
KeywordsIntestinal ion transport, Diarrhea, Intestinal absorption, Intestinal secretion
NIH grant R01DK041274 is acknowledged for financial support.
Diarrhea is a global health concern ranked second only to respiratory diseases in worldwide occurrence. In 2015, UNICEF estimated that half a million deaths per year from diarrhea occur among children under 5 years of age worldwide, which corresponds to 1400 childhood deaths every day. It is especially prevalent in the developing world, where mortality is related to dehydration, malnutrition, electrolyte disturbance, and the resultant acidosis. The highest mortality rate (80%) occurs during the first 2 years of birth. In comparison to developing countries, diarrhea-related mortality and morbidity is significantly lower in developed countries. In the United States, CDC reported 47.8 million diarrheal episodes with 3100 deaths annually, which quantify economic burden of US$150 million to the health-care sector. Additional estimates of the burden of diarrhea and its etiologies are produced annually as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. The latest study spanning years 1990–2015 has been recently summarized by Troeger et al. While the report was consistent with UNICEF data in terms of deaths under 5 years of age, the study also revealed encouraging trends with significant decreases in diarrheal diseases globally, albeit these improvement varied among countries. Among all the cases, the leading cause of diarrhea deaths was Rotavirus infection, followed by Shigella spp. and Salmonella spp., whereas in children under 5 years of age, the three most common etiologies responsible for childhood deaths were rotavirus, Cryptosporidium spp., and Shigella spp.
In the gastrointestinal tract, ionic balance, fluid absorption, and secretion are vital to maintain homeostasis allowing for the maintenance of a membrane potential, adequate nutrient intake, normal gut motility, protection against microbes, and epithelial cell viability. This homeostatic state relies on the normal physiological function of the small and large intestinal cells and a complex array of hormonal mechanisms that control gut motility as well as entry and exit of fluid into the gastrointestinal lumen. Although there is an individual variation in what can be considered a normal stool pattern, in health, infants pass 5–10 g/kg/24 h of stool output and adults range between 100 and 200 g/24 h. Any deviation from the norm will lead to fecal losses, deficits, and eventually disease. This chapter discusses the pathophysiology of different types of diarrhea, and reviews its various clinical manifestations.
Physiology of Intestinal Absorption and Secretion
Ingestion of fluids (~ 2 L) and secretion of salivary, gastrointestinal, biliary, and pancreatic juices (~ 6–7 L) result in 8–10 L of fluid containing 800 mmol sodium, 700 mmol chloride, and 100 mmol potassium passing through the small intestinal lumen daily. It is remarkable that in health, the small intestine absorbs all but 1.5 L and the colon absorbs the rest leaving approximately 100 mL of fluid to be lost in stool. The efficient mechanisms responsible for this absorptive capacity are due to the function of several transport proteins located at the brush border membrane of the small and large intestine ( Fig. 68.1 ).
The intestinal tract separates its secretory and absorptive functions spatially. The tip of the villous, which is the functional unit of the small intestine, harbors the highly differentiated absorptive cells, whereas the crypt epithelia represent undifferentiated secretory cells. Both active absorption and active secretion of fluid result from the selective ion permeabilities of the plasma membranes of the cells lining the intestine. Irrespective of whether a subject ingests a hypotonic or a hypertonic meal, the permeable proximal small bowel allows movement of water and electrolytes into the lumen rendering the meal isotonic with plasma as it reaches the proximal jejunum; thus, allowing optimal absorption.
Intestinal ion transport mechanisms play a significant role in determining overall fluid balance in the gut, namely chloride secretion, electroneutral sodium chloride absorption, and electrogenic sodium absorption. Intestinal chloride secretion is quantitatively the most important mechanism driving fluid secretion across the intestinal epithelium, which occurs primarily from the crypt cells throughout the gastrointestinal tract, and is stimulated by an increase in the intracellular level of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and calcium. These mediators inhibit the neutral sodium chloride entry and permit the entry of chloride into the cells through the basolateral membrane via the NKCC1, a sodium-potassium-2 chloride transporter (Na + -K + -2Cl − ). This transporter takes advantage of the low levels of intracellular sodium that are established by the basolateral sodium-potassium-ATPase. Cotransported potassium ions are recycled to avoid cellular depolarization and to maintain the driving force for chloride exit across the apical membrane through one of the several chloride channels, mainly cystic fibrosis transmembrane conductor regulator (CFTR) channel. An alternative Ca 2 + -activated Cl − channel (CaCCs)-mediated, and cAMP-independent chloride secretion mechanism also exists in intestinal epithelia. Although the molecular identity of CaCC still remains controversial, TMEM16 proteins (anoctamin, Ano), bestrophins (Best), and ClC-2 have been postulated as the potential candidates for CaCC in the gut. The transcellular transport of chloride drives the paracellular movement of sodium and water via the tight junctions ( Fig. 68.2 ).
In addition to chloride secretion, the sodium-potassium-ATPase pump on the basolateral membrane of enterocytes provides the driving force for the net transcellular movement of sodium, potassium, and bicarbonate along the length of the small intestine. Sodium and chloride absorption occurs through an electroneutral pathway, which is achieved by the coordinated regulation of the apical membrane sodium-hydrogen exchangers (NHEs), mainly NHE-2, NHE-3, and NHE-8, and the anion exchangers SLC26A3 (DRA), SLC26A6 (PAT1), and SLC4A9 (AE4). These sodium-hydrogen and chloride-bicarbonate exchangers seem to work in parallel. Bicarbonate and protons needed to drive this process are believed to be generated intracellularly by the activity of carbonic anhydrase. Sodium then exits the cell via the basolateral sodium-potassium-ATPase pump, which leads to a subsequent absorption of water via the paracellular route. This pathway accounts for nutrient-independent fluid absorption in the small intestine and is also an important component of colonic fluid absorption, particularly in the proximal colon. Nonetheless, a sodium-hydrogen exchange in the absence of a parallel chloride-bicarbonate exchange is observed in the duodenum and proximal jejunum and is responsible for the absorption of large amounts of bicarbonate derived from biliary and pancreatic secretions. Sodium is also absorbed in the small intestine through cotransport with various nutrients, mainly sugars (glucose and galactose) and amino acids. This is the primary mechanism for postprandial fluid absorption and is not altered by increased levels of cAMP.
Sodium absorption by colonic epithelial cells mainly in the distal colon occurs through an electrogenic pathway, regulated by aldosterone. In this pathway, sodium, driven by a low intracellular sodium concentration, enters via sodium-selective ion channels (ENaC) and is followed by the paracellular chloride and water movement through tight junctions. In a state of salt restriction, aldosterone contributes to epithelial sodium channel upregulation which leads to an increased sodium permeability of the distal colon and hence, an increased active sodium absorption.
A variety of hormones and neurotransmitters are synthesized locally in the intestinal mucosa and modify intestinal ion transport either directly by binding to receptors on the basolateral membrane of enterocytes or indirectly via the release of other effectors. Serotonin (5-hydroxytryptamine; 5-HT) and prostaglandin E 2 (PGE 2 ) are potent intestinal secretagogues. 5-HT plays a role in a local reflex that controls chloride secretion in response to epithelial mechanical stimulation. Activated enterochromaffin cells residing in the epithelium release 5-HT in response to epithelial deformation which in turn affects epithelial transport directly as well as indirectly through the activation of sensory nerves that release substance P, acetylcholine, and purine nucleotides. PGE 2 is synthesized by subepithelial elements and acts by increasing levels of cAMP, which mediates the secretory effect. Among the various neurotransmitters released in the intestinal mucosa, vasoactive intestinal polypeptide (VIP), acetylcholine (ACh), and substance P are predominantly secretory, whereas norepinephrine, somatostatin, neuropeptide Y, and enkephalins are mainly absorptive. Both norepinephrine and somatostatin activate the inhibitory G-protein Gi, which interferes not only with the activation of adenylate cyclase but also with one or more calcium-mediated events. A recent study revealed region-specific contributions of the pro-secretory neurotransmitters ACh, VIP, NO, substance P, ATP, and adenosine to the neural control of the epithelial ion transport. ACh was primarily involved in nerve-evoked secretion in the small intestine, whereas VIP and NO were more dominant in the large intestine.
Recent studies also indicate that the multifaceted calcium sensing receptor (CaSR), G protein-coupled cell surface receptor of class C type, is a key player in the regulation of intestinal fluid homeostasis. Highly expressed in GI tract, including both villus and crypt cells, CaSR impedes Cl − secretion and promotes Na + absorption when activated by extracellular cations, mainly by Ca 2 + and some amino acids. This antisecretory and proabsorptive effect of CaSR is attributed to the degradation of cyclic nucleotides (cAMP, cGMP) due to the activation of Ca 2 + -sensitive phosphodiesterases.
Definitions of Diarrhea
In certain pathophysiologic states, the finely tuned ionic-fluid exchange becomes dysfunctional as a result of the failure of compensatory pro-absorptive/antisecretory mechanisms. The excessive secretion of sodium and chloride ions followed by the release of a large amount of water into the colonic lumen results in diarrhea. Definitions of diarrhea include increased volume, altered consistency, and increased frequency of defecation. A stool output in excess of 10 g/kg/day in infants and children and 200 g/day in an adolescent or adult is considered abnormal. However, the measurement of stool fluid content is impractical and assessment of frequency is preferred for diagnostic purposes. Word Health Organization (WHO) defines diarrhea as the passage of more than three loose or watery stools in a 24 h period, but emphasizes the importance of change in stool consistency rather than frequency.
Diarrhea can further be divided into acute and chronic, allowing some categorization of causes and associated management. Acute diarrhea, the most common form, has an abrupt onset, usually due to infection. It is self-limited and resolves typically within 2 weeks with proper medication. When diarrhea persists for more than 14 days, the condition is referred to as chronic. Chronic diarrheas usually manifest secondary to inflammation in the digestive tract (e.g., inflammatory bowel diseases; IBD) or to functional bowel disorders such as irritable bowel syndrome (IBS), food allergies or intolerance, or parasitic infections ( Cryptosporidium , Giardia ). Different pathophysiological mechanisms causing diarrhea have been elucidated and often several mechanisms work simultaneously.
Pathophysiology of Diarrhea
Epithelial cells’ ion transport processes, in secretory diarrhea, are turned into a state of active secretion. Features of secretory diarrhea include a high stool volume output, a lack of response to fasting, absence of blood in stools, and a normal stool ion gap (100 mOsm/kg or less), indicating that nutrient absorption is intact ( Table 68.1 ). The mechanisms in this type of diarrhea include activation of intracellular mediators such as cAMP, cGMP, and intracellular calcium, which stimulate active chloride secretion from crypt cells and inhibit neutral coupled sodium chloride absorption ( Table 68.2 ). These mediators alter the paracellular ion flux because of toxin-mediated injury to the tight junctions. The most common cause of acute-onset secretory diarrhea is a bacterial infection of the gut. Several mechanisms may be at work. After colonization, enteric pathogens may adhere to or invade the epithelium; they may produce enterotoxins or cytotoxins. They may also trigger release of cytokines attracting inflammatory cells, which, in turn, contribute to the activated secretion by inducing the release of agents such as prostaglandins or platelet-activating factor. Coupled transport of sodium to glucose and amino acids is largely unaffected. Contrary, recent studies suggest rotavirus toxin NSP4 induce secretory diarrhea by inhibiting Na + absorption by the epithelial Na + channel ENaC and the Na + /glucose cotransporter SGLT1.
|Osmotic Diarrhea||Secretory Diarrhea|
|Stool volume||< 200 mL/day||> 200 mL/day|
|Response to fasting||Stops||Continues|
|Fecal Na +||< 70 mEq/L||> 70 mEq/L|
|Fecal Cl −||< 35 mEq/L||> 40 mEq/L|
|Fecal pH||< 5.6||> 6.0|
|Fecal osmotic gap||> 100 mOsm/kg||< 50 mOsm/kg|
|Fecal reducing substances||Positive||Negative|
|Activation of cyclic adenosine monophosphate|
|Bacterial toxins: Salmonella, Shigella, Campylobacter , Pseudomonas aeruginosa , Escherichia coli (heat-labile), enterotoxins of cholera|
|Hormones: vasoactive intestinal peptide, gastrin, secretin|
|Anion surfactants: bile acids, ricinoleic acid|
|Activation of cyclic guanosine monophosphate|
|Bacterial toxins: Escherichia coli (heat-stable), Yersinia|
|Bacterial toxins: Clostridium difficile|
|Neurotransmitters: acetylcholine, serotonin|
|Paracrine agents: bradykinin|
Occasionally, intestinal crypts undergo hyperplasia where the number of immature cryptal secretory cells increases to replace loss of absorptive cells. This cause of secretory diarrhea is noted in cases of enterocyte destruction and villous atrophy such as viral enteritis, celiac disease, and allergic enteropathy.
Osmotic diarrhea is caused by the presence of nonabsorbable solutes in the gastrointestinal tract ( Table 68.3 ). As such, stool output is proportional to the intake of these substrates and is usually not massive; diarrheal stools promptly regress with discontinuation of the offending nutrient, and the stool ion gap is high, exceeding 100 mOsm/kg ( Table 68.1 ). In fact, the fecal osmolality in this circumstance is accounted for not only by the electrolytes but also by the unabsorbed nutrient(s) and their degradation products. Because electrolyte absorption (Na + , K + , Cl − , HCO 3 − ) is unaffected by the osmotically active substances, stool water contains minute amounts of unabsorbed Na + and K + . This is the basis for the measurement and calculation of the fecal osmotic gap, a diagnostic test in the evaluation of patients with osmotic diarrhea.
|Malabsorption of water-soluble nutrients|
|Lactase deficiency (congenital or acquired)|
|Excessive intake of nonabsorbable solutes|
|Excessive intake of carbonated beverages|
Malabsorption and maldigestion can result due to the presence of osmotically active molecules within the intestinal tract. These molecules draw water into the lumen at a rate directly proportional to their concentration. This is further exacerbated in the colon where bacterial digestion of these molecules and fermentation to short-chain organic acids propagate the osmotic load and interfere with sodium absorption. A classic example is lactose malabsorption due to lactase deficiency.
Osmotic laxatives act via this mechanism. Polyethylene glycol 3350 (PEG) is poorly absorbed, not digested by human or bacterial enzymes, carries no electrical charge, and causes pure osmotic diarrhea. On the other hand, lactulose, a synthetic therapeutic disaccharide composed of galactose and fructose seems to be fermented at doses lower than organic acids, resulting in an osmotic load, but with higher doses diarrhea is mainly caused by a combination of organic acids and undigested carbohydrate.
Loss of resorptive area, destruction of epithelial cells, leaky tight junctions, and release of inflammatory mediators and products from immune cells that stimulate fluid secretion all have been implicated in the pathogenesis of inflammatory diarrhea. In contrast to many inflammatory-mediated diarrheal disorders, such as celiac disease, cholera, and toxigenic Escherichia coli infection, where inflammatory mediators elicit a net sodium, chloride, and fluid secretion, in Crohn’s disease (CD) and ulcerative colitis (UC), the main electrolyte transport abnormalities are decreased by sodium and chloride absorption in the absence of increased chloride secretion. This reduced sodium and chloride absorption in the inflamed intestine are attributed to perturbation in the expression and regulation of various ion channels and transporters involved, mainly ENaC, NHE3, DRA, and sodium-potassium-ATPase. In this context, Farkas et al. demonstrated impaired ENaC-mediated sodium absorption most likely due to reduced transcription in the distal colon of UC patients. In addition, Amasheh et al. clearly demonstrated only β and γ subunits but not α subunit of ENaC to be specifically downregulated in UC patients or ex vivo in surgically obtained colonic epithelial cells treated with proinflammatory cytokines TNFα and IFNγ. Relative to ENaC, the mechanism involved in the inhibition of NHE3 observed in inflammatory diarrhea is not well defined and may depend on the specific disease, segment involved, and/or the severity of inflammation. In a study by Sullivan et al. with patients with CD and UC, NHE3 protein and mRNA expression were decreased in sigmoid colonic biopsies and in ileal biopsies. Siddique et al. reported that NHE3 protein and Na + pump activity was decreased in UC and CD patient biopsies, but NHE3 mRNA was decreased only in CD and not in UC biopsies, thus highlighting the potentially different mechanism of NHE3 inhibition in CD and UC. Further studies in IL10 −/− colitis mice revealed blunted NHE3 activity, measured in the apical enterocytes within isolated colonic crypts, with unaltered NHE3 expression and localization. The investigators speculated that reduced expression of two key NHE3-regulatory proteins, SLC9A3 regulator 2 (SLC9A3R2/NHERF-2) and PDZ domain containing 1 (PDZK1), may be responsible for decreased NHE3 activity. Additional studies with UC patients showed a significant reduction in NHE3 activity despite the preserved protein and mRNA expression, thus arguing for a posttranslational mode of regulation of the antiporter activity. Clayburgh and colleagues demonstrated that endocytic removal of NHE3 from the brush border is the mechanism of TNF-induced Na + malabsorption. This is consistent with the observation that monoclonal antibodies to TNFα are effective in controlling diarrhea in some patients with IBD. Corticosteroids, on the other hand, stimulate electrogenic sodium absorption in addition to a general antiinflammatory effect, which would explain its immediate beneficial effects prior to mucosal healing.
Expression of another apical Na + /H + exchanger, NHE8, was also shown to be reduced in patients with UC and in murine DSS colitis, suggesting that it may contribute to inflammation-associated diarrhea in UC. Interestingly, somatostatin and its analogue octreotide, were able to prevent TNF-induced NHE8 inhibition in vitro, and reduced inflammation and diarrhea scores in mice with DSS colitis.
An early study of Yang et al. provided the first evidence to link altered DRA expression and UC in patients and reported a significant reduction in DRA mRNA expression and complete absence of DRA protein in the inflamed surface epithelium. A recent study correlated the alterations in DRA expression with Cl − /HCO 3 − exchange activity in crypts of 128 healthy individuals and 69 patients with IBD (with active UC and diarrheal symptoms). A robust reduction in Cl − absorption with a parallel decrease of 50% in DRA mRNA expression was observed in the surface cells of the colonic crypts in patients with UC. Further studies showed the involvement of TNF-α induced activation of NF-kB pathway in inhibiting DRA expression at the transcriptional level, which may partly contribute to IBD-associated diarrhea.
Altered Intestinal Transit
Diarrhea can result from an increased intestinal motility leading to a reduced intestinal transit time and poor absorption of water and substrates. Drugs, toxins as well as certain physiological states such as stress and anxiety may alter intestinal motility by directly affecting the enteric nervous system (ENS), which regulates gastrointestinal functions, for example, motility, water, and electrolyte secretion, blood flow as well as immune functions.
Cholera toxin illustrates the role of ENS in the pathogenesis of diarrhea. It evokes a net fluid secretion without affecting villous absorption or reaching cryptal cells. It stimulates the release of serotonin and prostaglandins from mucosal enterochromaffin-like cells, which in turn activate cholinergic and vasoactive intestinal peptide nerves resulting in a secretory response. On the other hand, the release of neuropeptides, substance P and calcitonin gene-related peptide from sensory neurons is the key event in Clostridium difficile toxin A-induced intestinal secretion. Structural changes of the ENS in IBD and other inflammatory disorders can also result in impaired gut motility and permeability.
Decreased intestinal transit time such as in malnutrition and intestinal pseudo-obstruction resulting in bacterial overgrowth can also manifest in diarrhea. This leads to deconjugation of bile salts, increase in intracellular mediator cAMP, and eventually increase in fluid secretion.
Loss of Functional Absorptive Area
Diarrhea results when mucosal injury or resection is such that the absorptive capacity of the intestine is diminished or overwhelmed. Short bowel syndrome is the classic example of such a state. It results from surgical resection of the bowel usually due to congenital malformations or irreversible injury to the gastrointestinal tract. Diarrhea results mainly when aggregate secretion by remnant proximal bowel exceeds absorptive capabilities of the remnant distal bowel. The region of bowel remaining after resection determines the adequacy of assimilation and the degree of malabsorption correlates with the length of remaining small bowel, its absorptive capacity, the presence or absence of the ileocecal valve and colon, and intestinal adaptation.
Microvillus inclusion disease (MVID) is a rare disorder which results in diarrhea presenting in the newborn period and requiring total parenteral nutrition to sustain life. The disorder is the result of mutations in Myo5B gene, causing a defect in trafficking of the brush border membrane proteins to the surface. Interestingly, individuals with mutations in either STX3, which encodes the transmembrane protein syntaxin-3, or STXBP2, which encodes Munc18-2, develop the clinical symptoms and cellular characteristics of MVID. Mutations in STX3 or STXBP2 give rise to disorders termed atypical MVID and familial hemophagocytic lymphohistiocytosis type 5 (FHL5), respectively. Recent data suggest that defects in apical recycling endosome function result in brush border microvillus atrophy and in the intracellular retention of enzymes and transporters that are required for the absorption of nutrients and ions by villus enterocytes, leading to the clinical phenotype of malabsorption and diarrhea in MVID and FHL5. Recently, elegant studies conducted to examine the effect of MYO5B loss in three separate mouse models (germline deletion, constitutive deletion, and inducible intestinal deletions in both adults and neonates) reveals induction of MYO5B loss in adult mice led to rapid development of diarrhea but without the formation of significant numbers of microvillus inclusions. The investigators suggested MYO5B deletion in the neonatal period replicates the human disease of microvillous inclusions.
Clinical Manifestations of Diarrhea
In diarrheal diseases ( Tables 68.4 and 68.5 ), several pathophysiological mechanisms often work simultaneously.
|Viral such as Rotavirus. Norwalk, Enterovirus, Calcivirus|
|Bacterial such as Escherichia coli, Shigella, Salmonella, Yersinia, Campylobacter, Clostridium difficile, Vibrio cholera|
|Parasitic such as Giardia lamblia , Cryptosporidium , Entamoeba histolytica|
|Brush border disorders|
|Microvillous inclusion disease|
|Primary lactase deficiency|
|Infectious (bacterial and parasitic)|
|Defective cellular immunity|
|Isolated IgA deficiency|
|Isolated amylase deficiency|
|Isolated lipase deficiency|
|Bile acid deficiency|
|Reduced mucosal surface area|
|Congenital malformations such as gastroschisis, omphalocele, small intestinal atresia, volvulus secondary to malrotation|
|Chylomicron retention disease/Anderson disease|
|Inborn errors of metabolism|
|Congenital sodium diarrhea|
|Congenital chloride diarrhea|
|Chronic nonspecific diarrhea|
|Adenoma (colon or rectum)|
Intestinal brush border disorders include congenital defects in villous structure, acquired disorders that reduce mucosal surface area and inflammatory disorders leading to villous atrophy. Patients with congenital disorders present with symptoms in the newborn period. The MVID is characterized by massive, life-threatening, watery diarrhea (250–300 mL/kg) and specific morphological enterocyte abnormalities. Ultrastructure analysis reveals severe villous atrophy on mature enterocytes with apical accumulation of numerous secretory granules in immature enterocytes in the absence of an inflammatory infiltrate. Light microscopy shows accumulation of Periodic acid-Schiff (PAS)-positive granules at the apical pole of enterocytes, together with atrophic band indicating microvillus atrophy and, in parallel, an intracellular PAS or CD10 positive line. Morphological abnormalities are seen in the small and large bowel. It manifests in the first few days of life (early-onset form) or in the first 2 months (late-onset form). Intestinal failure secondary to diarrhea is definitive. In Tufting enteropathy or intestinal epithelial dysplasia, on the other hand, the villous atrophy is moderate and localized to the small bowel. The prevalence seems higher in areas with high degree of consanguinity and in patients of Arabic origin. Parental consanguinity and/or affected siblings suggest an autosomal recessive transmission and mutations in the causative gene EpCAM, epithelial cell adhesion molecule, on chromosome 2p21 have been identified. Infants develop within the first few days after birth a watery diarrhea (100–200 mL/kg) persistent in spite of bowel rest and PN. Some infants are reported to have associated choanal, rectal, or esophageal atresia. Treatment for both conditions entails long-term total parenteral nutrition and ultimately small bowel transplantation. Long-term outcome is generally poor, due to metabolic decompensation, repeated states of dehydration, infectious and liver complications related to the parenteral nutrition, thus, timing of referral for intestinal transplantation becomes crucial.
Inflammatory villous injury may result from enteric infections or from allergic or immunologic responses to nutrients. Recovery from an acute infectious insult requires an intact immune system and appropriate nutritional support. If either is missing, a chronic diarrheal state ensues. Although Giardia lamblia , a protozoan, can infest healthy children and adults chronically, this usually is more a concern in immunodeficient children, particularly those with selective immunoglobulin (Ig) A deficiency. Patients with giardiasis experience diarrhea, steatorrhea, abdominal distention, abdominal pain, and even weight loss. G. lamblia infection causes epithelial transport and barrier dysfunction owing to downregulation of the tight junction protein claudin 1 and ZO1 and increased epithelial apoptosis via caspase 3 activation. Sodium-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhea in human chronic giardiasis comprise leak flux, malabsorptive, and secretory components. C. difficile , on the other hand, produces clostridial toxin, which increases intracellular calcium levels and modulates small GTP-binding proteins. Mucosal IL-8 and neutrophil recruitment are central to its pathogenesis. A common polymorphism in the IL-8 gene promoter was found to be associated with increased mean fecal IL-8 levels and increased susceptibility to C. difficile toxin-induced diarrhea.
Postinfectious diarrhea is the persistence of diarrhea beyond the expected duration of an infectious illness in an infant/child who was otherwise in apparent good health. Its pathogenesis is unclear but it has been suggested to be due to a delay in epithelial renewal leading to a deficiency in mature villi and a decrease in brush border enzymes and transport carriers. The greatest risk factor for progression to postinfectious diarrhea in a child with an acute diarrheal illness is preexisting malnutrition, which predisposes the individual to delayed crypt epithelial regeneration. It is the most common cause of protracted diarrhea in infancy. Its mildest form is simply due to transient lactose intolerance. Enteral nutrition becomes essential for mucosal healing and hydrolyzed formulas may allow for an early refeeding of the injured intestine. In adults, postinfectious IBS is often seen following recovery from C. difficile and other bacterial infections. These patients can present with altered gut immune function represented by an increase in lymphocyte infiltrates and inducible nitric oxide synthase in feces.
Eosinophilic gastroenteropathy is characterized by prominent eosinophilic infiltration through a variable depth of one or more gastrointestinal sites with or without peripheral eosinophilia. The extent of eosinophilic infiltration of the gastrointestinal wall varies from mucosal to transmural and serosal involvement. Diagnosis requires the presence of gastrointestinal symptoms, demonstration of gastrointestinal eosinophilia by biopsy, and exclusion of other known causes of tissue eosinophilia. Many studies have pointed toward eosinophils as the major offenders; however, the exact functional role of eosinophils in the pathogenesis of eosinophilic gastrointestinal disorders remains unclear. The roles of T-helper-2 cytokines and other mediators, such as eotaxin-1 and interleukin-5, have gained significant importance in the pathobiology of eosinophilic gastrointestinal disorders. Systemic steroids produce symptomatic and histologic improvement in the number of eosinophils in the GI tract, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and antiimmunoglobulin E, along with other targets in the immune pathway, are currently being explored.
Celiac disease is an immune-mediated enteropathy caused by permanent sensitivity to gluten in genetically susceptible individuals. It is a multiorgan inflammatory disorder that can present at any age and has largely emerged as a worldwide public health problem. With a prevalence of 1% in the western populations, celiac disease is one of the most common inflammatory disorders of the small intestine. It should be considered in any child or adult with symptoms of diarrhea, failure to thrive, abdominal distention, dermatitis herpetiformis, dental enamel defects, short stature, delayed puberty, osteoporosis, and persistent iron deficiency anemia. It also occurs in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, and in first degree relatives of individuals with celiac disease. Gluten protein is derived from a group of cereal grains that include wheat, rye, and barley. Pure oats are not considered an offending agent although oats in the United States are usually milled with other grains that contaminate the mixture with gluten and may cause problems. In early disease, there is a dysfunction of the intercellular tight junctions, which together with an exaggerated passage through the cells, leads to an excessive amount of gluten and gliadin fragments in the lamina propria. These molecules will then stimulate the innate immune system leading to the production of proinflammatory cytokines that establish an early inflammatory response and, therefore, cell damage. The transglutaminase-2 leaking out from damaged cells deamidates gliadin fragments that are then recognized by antigen-presenting cells bearing HLA-DQ2/DQ8 molecules triggering further damage to the intestinal mucosa. The gold standard for diagnosis is a small bowel biopsy documenting villous injury. Because histologic changes in celiac disease can be patchy, multiple biopsies obtained from the bulb, second or more distal part of the duodenum are recommended. Once a diagnosis is made, the only scientifically proven treatment remains a gluten-free diet for life.
The IBDs comprise a heterogeneous group of chronic inflammatory disorders of the intestinal tract, the cause(s) of which is still unknown. However, active research on the pathophysiology of IBD, over the last decades, revealed that the chronic inflammatory reaction of the intestinal mucosa is directed against the microbiota of the gut in susceptible individuals. Genetic studies and more recently genome-wide association studies (GWAS) have identified over 50 susceptibility genes, which confer an increased risk of developing IBD. Most of these genes code for molecules of the innate or adaptive immune system, such as NOD2, ATG16L1, STAT3, or IL23-R, as well as factors involved in epithelial integrity. These genetic data helped to identify key checkpoints essential to maintain immune homeostasis in the intestinal mucosa, and their failure might thus contribute to disease development. Experimental models of colitis emphasize the key role of uncontrolled T-lymphocyte responses in the perpetuation of mucosal inflammation. There are several epidemiological data indicating that the incidence of pediatric IBD, mainly Crohn’s disease, is still increasing over the last decades, with indicators of more extensive and more severe disease presentations in children compared with adults. The pathogenesis of diarrhea in IBD is multifaceted. In addition to the inflammation seen in CD that results in alteration of sodium, chloride, and water absorption, patients may have bile-acid diarrhea due to ileal dysfunction from inflammation or resection or in the case of increasing fecal bile acid losses steatorrhea may ensue.
In diseases with defects of innate immunity such as chronic granulomatous disease of childhood and adaptive immunity such as severe combined immunodeficiency syndrome (SCIDS) IBD develops in 17% and 30%, respectively. Poorly understood autoimmune derangements lead to generalized enteropathy in these conditions manifesting as diarrhea. Histology of the small intestine shows villous atrophy and inflammatory infiltrates indistinguishable from celiac disease. Gluten free diet, however, has no effect but in some a hypoallergenic formula controls symptoms.
Autoimmune enteropathy is a rare disorder characterized by severe and protracted watery diarrhea early in life not responsive to dietary restriction and defined by the presence of circulating antibodies to enterocytes along with a duodenal mucosal biopsy that shows total villous atrophy, crypt hyperplasia, and a dense lymphoplasmacytic infiltrate in lamina propria. Unlike celiac disease, there is a relative paucity of intraepithelial lymphocytes. Treatment consists of nutritional support with immunosuppressive therapy.
Microscopic colitis is common in elderly patients with a median age of onset of 68 years. Its two forms are lymphocytic and collagenous colitis. It is thought to be due to a luminal antigen, dietary or microbial, that induces an increase in intraepithelial lymphocytes and inflammatory cells in the lamina propria.
Intracellular Lipid Transport and Metabolism Defects
Chylomicron retention disease, also called Anderson disease, is a rare autosomal recessive disease caused by mutation of SAR1B gene encoding the Sar1b protein involved in chylomicron transport from the endoplasmic reticulum to the Golgi apparatus. Clinical manifestation includes failure to thrive, diarrhea, and fat malabsorption resulting in decreased total cholesterol and normal triglycerides. SAR1B mutation induces an accumulation of prechylomicron transport vesicles in the enterocyte cytoplasm, as seen on intestinal biopsies. In the fruit fly ( Drosophila melanogaster ), Sar1b is involved in the trafficking of Crumbs, a protein that controls apical-basal epithelial cell polarity in the intestine. Whether SAR1B mutations in CMRD also affect the trafficking of apical brush border proteins in enterocytes and thereby contribute to defective (lipid) absorption remains to be investigated.
Familial hypobetalipoproteinemia (FHBL), the only congenital diarrheal disorders associated with enterocyte defects that is dominantly inherited, is associated with mutations in the APOB gene, encoding apolipoprotein B, which, together with triglycerides and other lipids, makes up the nascent chylomicron. Abetaliproteinemia is associated with mutations in the MTTP gene, which encodes microsomal triglyceride transfer protein (MTTP). The MTTP catalyzes the transfer of triglycerides to nascent ApoB particles in the endoplasmic reticulum.
Defects in Bile Acid Micellar Solubilization
Moderate steatorrhea can occur in any hepatobiliary disorder leading to bile acid deficiency. This can result from a defect in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulate hepatic bile acid (BA) synthesis or from genetic variations that affect the proteins involved in BA enterohepatic circulation. This leads to a decreased secretion of bile salts into the duodenum below the critical micellar concentration of 3 mmol/L, thus, impairing the absorption of fats and fat-soluble vitamins. Increased enteric bacterial deconjugation, reduction in ileal reabsorption due to inflammation or resection, or the presence of medications that bind bile acids can also lead to bile acid deficiency. In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the sodium taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent manner across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently identified heteromeric organic solute transporter, OSTalpha-OSTbeta.
Cystic fibrosis (CF) is a major cause of pancreatic exocrine failure in children. It is an autosomal recessive disorder caused by a mutation in the CFTR gene on chromosome 7 leading to a defective cyclic-AMP dependent chloride channel function. This results in reduced volumes of more acidic secretions and has been suggested to lead to the precipitation of highly concentrated protein-containing secretions, resulting in obstruction and organ damage. Even though pulmonary disease is the major cause of morbidity and mortality, majority of patients (85%–90%) have pancreatic insufficiency and suffer from gastrointestinal symptoms. Clinical signs of pancreatic insufficiency develop when less than 10% of normal pancreatic enzyme activity is present in the duodenum. It is the genotype that predicts, with high probability, the development of exocrine pancreatic insufficiency in CF. Patients who carry two severe mutations develop pancreatic insufficiency. A small proportion of such individuals are, nevertheless, pancreatic sufficient at diagnosis, and they experience a gradual transition to pancreatic insufficient status.
Other causes of pancreatic insufficiency include chronic pancreatitis, Shwachman-Diamond-Oski syndrome, Johanson-Blizzard syndrome, and Pearson syndrome. Shwachman-Diamond, the second most common cause of pancreatic insufficiency, is an autosomal recessive disorder characterized by exocrine pancreatic failure, skeletal abnormalities, and bone marrow dysfunction, mainly cyclic neutropenia. Pancreatic insufficiency in this condition is probably due to failure of acinar tissue to develop normally in utero. Thus, pancreatic tissue is replaced by fatty deposition. Over time, however, pancreatic hypoplasia is reversed and there is an increase in normal pancreatic tissue volume along with possible improvement in pancreatic function. Johanson-Blizzard syndrome is characterized by hypoplasia of the alae nasi, deafness, imperforate anus, urogenital malformations, and dental anomalies. As with Shwachman-Diamond syndrome, the pancreas is replaced with fatty tissue. Endocrine abnormalities such as diabetes and hypothyroidism have been associated with this condition. Pearson syndrome, on the other hand, results from deletions in mitochondrial DNA. Patients have pancreatic insufficiency and refractory sideroblastic anemia. Death frequently ensues in infancy or early childhood due to sepsis or metabolic disarray.
Zollinger-Ellison syndrome (ZES) is a rare pancreatic disorder characterized by hypergastrinemia and gastric acid hypersecretion causing peptic ulcer disease, diarrhea, and weight loss. Elevated serum gastrin from the gastroenteropancreatic neuroendocrine tumor results in a stimulation of parietal cells in the stomach. The increased rate of gastric acid secretion causes a volume load that cannot be fully reabsorbed by the distal small intestine and colon. This volume overload is compounded by pancreatic bicarbonate secretion activated by the abundant acid in the duodenum. Pancreatic bicarbonate secretion thus increases and typically cannot keep up with the excess acid production in the patient with ZES. This causes an acidic environment in the duodenum which inactivates pancreatic digestive enzymes. Excess acid interfering with pancreatic enzymes disrupts the emulsification of fat by bile acids, and damages intestinal epithelial cells and villi. In addition to the increased fluid volume and solute volume, the cellular damage impedes normal sodium and water absorption in the small intestine.
Lymphatic Flow Defects
Intestinal lymphangiectasia is characterized by dilated intestinal submucosal and subserosal lymphatics, diarrhea, steatorrhea, protein losing enteropathy, growth retardation, hypoalbuminemia, edema, and lymphopenia. It may be primary due to congenital abnormalities in the lymphatic vessels of the intestinal tract or secondary to a number of disorders such as congestive heart failure, following Fontan procedure for hypoplastic left heart syndrome, liver cirrhosis, lymphatic tumors, or Behcet disease. Perturbation of lymphatic flow results in malabsorption of fat-soluble vitamins and long-chain dietary fats. Medium- and short-chain fatty acids can still be absorbed and transported directly through the mesenteric venous blood to the liver. Poor lymphatic drainage, however, produces increased intestinal lymphatic pressure and leakage of lymph into the intestinal lumen with consequent loss of proteins and lymphocytes. Patients can have generalized or even asymmetric edema. In addition to addressing the underlying cause in secondary intestinal lymphangiectasia, treatment for primary and secondary cases often includes a high-protein, low-fat diet given mostly in the form of medium-chain triglycerides. Octreotide has been helpful but should probably be reserved for patients who fail dietary therapy. Surgery is reserved for palliation of large chylous ascites or resection of isolated lesions. In the cases of intestinal lymphangiectasia with protein losing enteropathy secondary to Fontan procedure, medical management has included anticoagulation to improve hemodynamics with subcutaneous high-molecular-weight heparin and stabilization of the intestinal cell membrane with high dose steroids.
This term refers to the detrimental side effects of medication and accounts for approximately 7% of all adverse drug effects. Over 700 drugs have been implicated in causing diarrhea. This includes laxatives, antacids and other heartburn medications, antibiotics, chemotherapy and antiinflammatory drugs. It can be either acute or chronic in nature, and the severity of diarrhea depends on the drugs dosage, duration, and frequency of administration. Antibiotic-associated diarrhea is one of the most common forms that occurs in up to a third of all patients treated with antibiotics, especially those with broad spectrum such as clindamycin, amoxicillin, ampicillin, and cephalosporins. It typically results from a disturbance of protective gut microbiota leading to undesirable growth of opportunistic pathogens particularly C. difficile , eliciting severe, watery, and often bloody diarrhea associated with pseudomembranous colitis. Noninfectious mechanism of pathogenesis includes direct toxicity of antibiotics, and metabolic alterations related to dysbiosis caused by antibiotic treatment. The present approaches to mitigate antibiotic-associated diarrhea episodes effect include dose reductions, treatment delays, discontinuation of therapy, and rehydration.
Inborn Errors of Metabolism
Congenital chloride diarrhea is a rare genetic disease caused by mutations in the gene encoding the solute-linked carrier family 26-member A3 (SLC26A3) protein, which acts a plasma membrane anion exchanger for chloride and bicarbonate. The main clinical symptom is lifelong watery diarrhea with high chloride content and low pH, leading to dehydration and hypochloremic metabolic alkalosis. Long-term prognosis is generally favorable, but complications such as renal disease, hyperurecemia, inguinal hernias, spermatoceles, and decreased fertility are possible. Butyrate therapy is beneficial for those patients.
Congenital sodium diarrhea (CSD) is another rare disorder characterized by persistent severe diarrhea with increased sodium fecal excretion, and consequently, hyponatremia and metabolic acidosis, with high mortality rate.
Holmberg and Perheentupa and Booth et al. described CSD as resulting from defective NHE (OMIM 270420). Although homozygosity mapping and multipoint linkage analysis studies in four candidate regions known to contain key NHE genes have shown that CSD is an autosomal recessive disorder unrelated to mutations in the NHE1, NHE2, NHE3, and NHE5, more recent study showed that classical, nonsyndromic CSD may indeed result from a loss of function of NHE3. In a small cohort of patients, mutations (point, missense, and truncation) in the NHE3-encoding SLC9A3 gene occurred in half of the studied CSD cases. About one-third of CSD the patients display a syndromic form associated with a pattern of congenital malformations such as choanal atresia, hypertelorism and corneal erosions, double kidney, and cleft palate. The syndromic form of CSD is thought to arise from loss-of function mutations in SPINT2 gene encoding a Kunitz-type serine-protease inhibitor. Although its relationship with epithelial NHE is not known, SPINT2 protein is involved in the regulation of the epithelial sodium channel (ENaC), which is critical for sodium reabsorption in the distal colon. The activity of ENaC in the distal colon is dependent on its proteolytic activation by a system consisting of two serine proteases, matriptase and prostasin, and their inhibitor SPINT2. Inhibition of NHE3 along with stimulated CFTR-mediated Cl − secretion due to elevated intracellular cGMP may be responsible for the sporadic cases of CSD associated with constitutively activating and hyperstimulating mutations in receptor guanylate cyclase C, encoded by the GUCY2C gene.
Acrodermatitis enteropathica is a very rare autosomal recessive disease characterized by severe and generalized zinc deficiency. It is caused by a defective intestinal zinc absorption especially in the duodenum and jejunum, two key sites for zinc homeostasis. It typically occurs in early infancy and is characterized by periorificial and acral dermatitis, alopecia, and diarrhea. Mutations in the AE SLC39A4 gene located at 8q24.3 that encodes a zinc-specific transporter belonging to the zinc/iron-regulated transporter-like family has been identified. The SLC39A4 mutations spread over the entire gene and include many different types of mutations. Zinc supplementation must be continued to prevent relapse. Some of the AE-like disorders are associated with severe zinc deficiency induced by dietary factors (low dietary intake of zinc, phytate-rich diet), physiological status requiring higher zinc intake (pregnancy or lactation), digestive disease (malabsorption syndromes, pancreatic or hepatic insufficiencies), renal insufficiency, or iatrogenic factors (penicillamine or chlorthiazide therapy).
A newly discovered disorder, named “enteric anendocrinosis” and characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells, is caused by loss-of-function mutations in NEUROG3. It was first described by Wang and colleagues in three patients who presented during the first several weeks of life with vomiting, diarrhea, dehydration, and a severe hyperchloremic metabolic acidosis after the ingestion of standard cow milk-based formula. Small bowel biopsy revealed a normal villous structure and no pathologic infiltration of inflammatory cells but showed profound dysgenesis of the enteroendocrine cells. All patients required total parenteral nutrition.
Intestinal Brush Border Enzyme Deficiencies and Transport Defects
Disaccharidase deficiencies cause persistence of the undigested carbohydrate along an isotonic luminal content into the colon, where bacteria ferment undigested sugars into small-chain fatty acids, stimulating sodium and water absorption. The most common type of carbohydrate malabsorption is lactose malabsorption due to “adult-onset” lactase deficiency. While congenital lactase deficiency is rare, reported mostly in Finland, the “adult-onset” form is very common beginning as early as 2 years of age in some racial groups. Its prevalence can reach 80%–100% in Asians, African-Americans, and families of Mediterranean ancestry. It has been postulated that a genetically controlled “switching off” of the lactase gene occurs in susceptible individuals. Although lactase does not function as an inducible enzyme, continued exposure to milk products beyond infancy can, to a certain degree, delay the age of onset of symptoms in genetically determined lactase deficiency.
Sucrase-isomaltase deficiency is the most common congenital enzyme deficiency in carbohydrate maldigestion. It was first described in 1961 by Weijers and colleagues. It can present with diarrhea, bloating, and cramps in infancy when sucrose-containing fruits are introduced or can manifest as intermittent symptoms in an older child. The diagnosis is established when a histologically normal duodenal or jejunal biopsy demonstrates deficient sucrase-isomaltase activity. Treatment is strict avoidance of sucrose or the use of the commercially available preparation of sucrase prior to any sucrose ingestion.
Glucose and galactose are two monosaccharides that are absorbed via energy-dependent specific carrier protein known as SGLT1. Glucose-galactose malabsorption is an autosomal recessive disease that presents with life-threatening diarrhea from day upon ingestion of breast milk, mutations in SGLT1 are responsible for loss of function of the glucose-galactose carrier. In many patients, clinical tolerance to the offending carbohydrates improves with age despite the fact that the transport defect persists. Fructose absorption, on the other hand, occurs via facilitated transport through the carrier GLUT5. Isolated fructose malabsorption is rare and its defect has not yet been established.
Lysinuric protein intolerance (LPI) is a rare inherited defect of cationic amino acid (lysine, arginine, and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y(+)LAT1 transport protein. Impairment of intestinal dibasic amino acids absorption and renal reabsorption causes a metabolic derangement characterized by diarrhea along with low plasma concentration of dibasic amino acids, and dysfunction of the urea cycle leading to hyperammonaemia, orotic aciduria, and protein aversion.
An important cause of chronic diarrhea is the presence of colonic and extra-colonic-associated neoplasms. Carcinoids secrete hormones such as vasoactive intestinal peptide (VIP), 5-HT, substance P, bradykinin and prostaglandins, all of which have a pro-secretory effect. The VIP increases cAMP levels while kinins act at the basolateral membrane sodium-potassium ATPase and the luminal CFTR chloride channels to increase luminal sodium and chloride concentration. Profuse diarrhea develops in 30% of patients with medullary carcinoma of the thyroid because of secretion of calcitonin, another secretagogue. Secretory villous adenomas of the colon and rectum are characterized by dehydration, prerenal azotemia, hyponatremia, hypokalemia, metabolic acidosis, and obtundation. Both cAMP and PGE2 are thought to be responsible for the pathogenesis of this disorder.
Diabetic diarrhea occurs in 20% of diabetics and is considered to be a manifestation of autonomic neuropathy with decreased function of the adrenergic and ENS. This makes diabetes the most common systemic disease-causing diarrhea.
Chronic Nonspecific Diarrhea
Toddler’s diarrhea or chronic nonspecific diarrhea is a benign condition in a healthy thriving child. Although the precise pathophysiology remains to be elucidated, evidence suggests that toddler’s diarrhea primarily is a gut motility disorder, modulated by dietary factors. It has been shown in small intestinal motility studies that fasting activity is normal while postprandial motility is abnormal. Although the role of low-fat diets has since long been established, the liberal consumption of fruit juices and soft drinks is considered an equally important factor. Another mechanism may be the dumping of bile acids and hydroxy fatty acids into the colon, leading to cholerrheic diarrhea. This was substantiated by stool examination. The diarrhea is often watery and at times contain undigested food particles. Normalization of the child’s diet, especially with regard to fat, fiber, fluids, and fruit juices, usually suffices to attain resolution of the diarrhea.